Classifications

• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B82—NANOTECHNOLOGY
  • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
  • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
  • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
  • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin

Definitions

• This invention relates to new compounds obtained by complexing folinic acid with a cyclodextrin chosen from ⁇ , ⁇ , ⁇ , dimethyl- ⁇ and hydroxypropyl- ⁇ cyclodextrin, their preparation and the relative pharmaceutical compositions.
• Folinic acid of formula (I) is used as an antidote for excessive doses of folic acid antagonists and to counteract the side effects induced by aminopterin (4-­aminopteroylglutamic acid) and methotrexate (4-amino-N10-­methylpteroyl-glutamic acid).
• Folinic acid is also indicated for all anemic forms deriving from folic acid deficiency due to increased requirement, reduced utilization, or insufficient dietary content of folates.
• Folinic acid has however a drawback in that it is unstable in an acid environment, so that a reduction in its therapeutic activity can be encountered by oral administration of this active principle.
• the present invention provides complexes of folinic acid of formula (I) or its pharmaceutically acceptable cation salts with a cyclodextrin chosen from ⁇ , ⁇ , ⁇ , dimethyl- ⁇ and hydroxypropyl- ⁇ cyclodextrin.
• the folinic acid and the cyclodextrin are present in a molar ratio of between 1:1 and 1:4.
• folinic acid salts used for preparing the complexes according to the present invention, calcium folinate is preferred.
• the present invention also relates to the preparation of the complexes according to the present invention, which can be done by three different methods:
• the complexes of the present invention have more favourable properties than the drug used as such.
• the new compounds have the same toxicity as calcium folinate (LD50 greater than 7000 mg/kg in the mouse), but in compensation have superior antianemic activity and greater stability in an acid environment.
• the following table shows the stability of the folinic acid- ⁇ -­cyclodextrin complex in a molar ratio of 1:3 compared with that of calcium folinate used as such, in solutions of pH 2.0.
• the present invention further provides pharmaceutical compositions for treating all forms of folate deficiency which are suitable for oral administration and contain as active principle the complexes of the present invention in combination with excipients normally used in pharmaceutical compositions.
• Liquid oral compositions such as syrups (ready or extemporaneous) and solid oral compositions such as tablets, sugar coated pills, soft or hard capsules or single dose sachets are particularly suitable for the designated therapeutic use.
• compositions according to the present invention can be administered once or twice per day in doses of between 5 and 15 mg depending on the gravity of the symptomatology.
• the mixture is stirred until a solution forms.
• the solution is dried by lyophilization or spray drying to obtain 26 g of a product with a folinic acid concentration of 17%.
• the mixture is stirred until a solution forms.
• the solution obtained is dried by lyophilization or spray drying.
• the mixture is stirred until a solution forms.
• the solution obtained is dried by lyophilization or spray drying.
• the mixture is stirred until a solution forms.
• the solution obtained is dried by lyophilization or spray drying.

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• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Engineering & Computer Science (AREA)
• Life Sciences & Earth Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Animal Behavior & Ethology (AREA)
• Epidemiology (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Veterinary Medicine (AREA)
• Nanotechnology (AREA)
• General Engineering & Computer Science (AREA)
• Biotechnology (AREA)
• Medical Informatics (AREA)
• Molecular Biology (AREA)
• Crystallography & Structural Chemistry (AREA)
• Biophysics (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicinal Preparation (AREA)

Applications Claiming Priority (2)

Publications (1)

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ID=11192944

Family Applications (1)

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Cited By (8)

Citations (1)

• 1989
  • 1989-10-31 IT IT02219989A patent/IT1237509B/it active IP Right Grant
• 1990
  • 1990-10-29 EP EP90120676A patent/EP0427078A1/en not_active Withdrawn

Patent Citations (1)

Non-Patent Citations (3)

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